Education and employment among patients with childhood-onset epilepsy in adulthood: A population-based cohort study.

OBJECTIVE: This study explored the association of childhood-onset epilepsy (COE) with educational attainment, adulthood employment, and income. METHODS: A population-based cohort of 312 children with COE was identified from Tampere University Hospital, Finland. Population Register Center formed a matched random population sample of 1248 children without COE as a reference cohort. The two cohorts were linked to the Statistics Finland database to obtain information on educational attainment, employment status, and income. Fisher's exact test was used to compare employment and graduation. Independent samples t-test was used for analyzing graduation grades and the Mann-Whitney test was used for analyzing yearly income. Results were stratified by sex and disability. RESULTS: During a follow-up of 25 years, a substantially higher proportion of the patients never entered the workforce, 37 % (109/312) compared with 4 % (44/1248) for the referents without COE (p < 0.001). A two-fold difference was observed for COE patients without other disabilities (7.7 %, 13/169, p = 0.01). No clear difference was found in long-term employment between the COE without disabilities and the referents (67 %, 114/169 versus 74 %, 920/1248, p = 0.087). The patients with COE had worse lower secondary school graduation grade averages (7.36 vs 7.6, p = 0.004) and graduation rates (64 % vs 98 %, p < 0.001), the patients without disabilities had similar results to referents (7.43, p = 0.07, 98 %). Of the patients with COE, 18 % graduated from college compared to 38 % of the referents (p < 0.001). The median income was lower in males and females with COE of all ages compared to the referents. The COE patients without additional mental or physical disabilities had income comparable to the healthy referents. 143 patients (46 %) had additional disabilities. SIGNIFICANCE: Patients with COE have lower educational attainment, stable employment, and income. Patients without disabilities also have an increased risk of unemployment, but those capable of entering the workforce have stable careers with earnings comparable to the rest of the population.

Neuropsychological group rehabilitation on neurobehavioral comorbidities in children with epilepsy.

Neurobehavioral comorbidities, particularly attention-deficits, are common in children with epilepsy (CWE). Neurobehavioral problems are manifested in school performance, peer relations, and social competence. Although the high prevalence of these comorbid behavioral problems is fully recognized, there remains to be a lack of studies on the interventions targeted for CWE. A manualized neuropsychological group intervention, Rehabilitation of EXecutive Function and ATtention (EXAT) has been developed for school-aged children (aged 6-12 years) with executive function (EF) and attention-deficits. This study aimed to explore the effects of EXAT on parent- and teacher-rated attention and behavior problems in CWE compared with children with the diagnosis of attention-deficit hyperactivity disorder (ADHD) and children with no formal diagnosis but prominent deficits in EF and attention. Forty-two children attending in neuropsychological group rehabilitation EXAT between the years 2006 and 2017 participated in this retrospective registry study. The CWE group consisted of 11 children, the ADHD group with 16 children, and EF/attention group consisted of 15 children with EF attention and/or problems without diagnosis of ADHD. The CWE group did not differ from the other two study groups (ADHD and no formal diagnosis) before the EXAT intervention. This indicates that attention problems in CWE are similar to those with diagnosed ADHD. The results were promising for applying structured multilevel intervention for CWE and neurobehavioral comorbidities. Lack of group differences between the groups participating EXAT suggests similar intervention effects between CWE, ADHD, and those with less severe EF and attention problems. In parent ratings, intervention effects were higher in hyperactivity and oppositional behavior for children with attention problems and without epilepsy. Parents in the CWE group reported no effects except for one subscale related to hyperactivity. However, teachers reported consistently positive intervention effects for both inattention and hyperactivity-impulsivity along with anxiety and emotional lability. The results suggest that neurobehavioral comorbidities in CWE could be targeted in neuropsychological group intervention. In conclusion, CWE seem to benefit from interventions and behavior modification techniques first developed for children with ADHD.

Fertility and marital status in adults with childhood onset epilepsy: A population-based cohort study.

OBJECTIVE: Our objective was to explore the association of childhood onset epilepsy (COE) and clinical factors on marital status and fertility in adulthood. METHODS: We identified a population-based cohort of 307 individuals with COE treated in the Tampere University Hospital district with an inception date of December 31, 1992. A matched reference cohort of 1244 individuals without COE was established as a random sample of the population in the study area through the Population Register Center (PRC). The PRC also provided data on marriages and offspring up to 2018. Fertility and marriage analysis was done by calculating the time until first child and marriage. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated with Cox regression for follow-up spanning up to January 2018. RESULTS: Patients with COE had lower fertility rates (32.2% vs 57.3% any offspring, HR = 0.47, 95% CI = 0.38-0.58) and fewer marriages (28.3% vs 49.7% ever married, HR = 0.49, 95% CI = 0.39-0.61) than the referents without COE during 25-year follow-up. The largest impact was in patients with COE who had any disability (10.1% any offspring, HR = 0.20, 95% CI = 0.10-0.41; 6.5% ever married, HR = 0.11, 95% CI = 0.06-0.21), symptomatic etiology of epilepsy (13.1%, HR = 0.18, 95% CI = 0.11-0.31; 12.1%, HR = 0.21, 95% CI = 0.12-0.36), onset of epilepsy before 2 years of age (HR = 0.20, 95% CI = 0.12-0.31; HR = 0.29, 95% CI = 0.18-0.46), and high seizure frequency after start of treatment (HR = 0.13, 95% CI = 0.06-0.28; HR = 0.20, 95% CI = 0.10-0.41). Patients with COE without any disabilities had only slightly lowered fertility (HR = 0.76, 95% CI = 0.61-0.95) and a nonsignificant reduction in marriages (HR = 0.80, 95% CI = 0.64-1.02). SIGNIFICANCE: COE was associated with a lower chance of finding a partner at adulthood and having fewer children. The extent of such effect varied between patient subgroups.

Variants p.Q1236H and p.E1143G in mitochondrial DNA polymerase gamma POLG1 are not associated with increased risk for valproate-induced hepatotoxicity or pancreatic toxicity: A retrospective cohort study of patients with epilepsy.

OBJECTIVE: Previous studies have suggested that heterozygous variants p.Q1236H and p.E1143G in mitochondrial DNA polymerase gamma (POLG1) increase the risk for liver injury for patients on valproate (VPA) therapy. We assessed the prevalence of these common variants and seven other pathogenic mutations in POLG1 and determined the occurrence of VPA-induced hepatotoxicity (VHT) or pancreatic toxicity in a cohort of patients with epilepsy. METHODS: Patients with epilepsy (N = 367) were retrospectively identified from medical record files and screened for mutations in POLG1. Patients who had received VPA monotherapy and carried either of the two variants, p.Q1236H or p.E1143G, without other pathogenic mutations in POLG1 (n = 33, variant group) and patients without these variants (n = 28, nonvariant group) were included in the study. Clinical data on epilepsy, characteristics of VPA treatment, risk factors for VHT, laboratory data on liver and pancreas functions, and adverse effects were collected. RESULTS: A total of 122 patients had either the POLG1 p.Q1236H (n = 99) or p.E1143G (n = 24) variant in the heterozygous or homozygous state. Transient liver dysfunction was identified in three (n = 33, 9.1%) variant group patients and in one (n = 28, 3.6%) nonvariant group patient (P = 0.62). Mild to moderate elevations in liver enzymes were encountered in both groups. Furthermore, two patients on VPA polytherapy developed acute pancreatitis, and two pediatric patients with heterozygous p.Q1236H variants and mutations in IQSEC2 and GLDC, respectively, had elevated levels of VPA metabolites in urine, elevated plasma glycine, and/or increased acylglycine excretion. SIGNIFICANCE: POLG1 p.Q1236H and p.E1143G variants could not be identified as statistically significant risk factors for VHT or pancreatic toxicity. We suggest that VPA treatment could be suitable for patients who harbor these common variants in the absence of other pathogenic mutations in POLG1.

Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A.

Epilepsy comprises several syndromes, amongst the most common being mesial temporal lobe epilepsy with hippocampal sclerosis. Seizures in mesial temporal lobe epilepsy with hippocampal sclerosis are typically drug-resistant, and mesial temporal lobe epilepsy with hippocampal sclerosis is frequently associated with important co-morbidities, mandating the search for better understanding and treatment. The cause of mesial temporal lobe epilepsy with hippocampal sclerosis is unknown, but there is an association with childhood febrile seizures. Several rarer epilepsies featuring febrile seizures are caused by mutations in SCN1A, which encodes a brain-expressed sodium channel subunit targeted by many anti-epileptic drugs. We undertook a genome-wide association study in 1018 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 7552 control subjects, with validation in an independent sample set comprising 959 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 3591 control subjects. To dissect out variants related to a history of febrile seizures, we tested cases with mesial temporal lobe epilepsy with hippocampal sclerosis with (overall n = 757) and without (overall n = 803) a history of febrile seizures. Meta-analysis revealed a genome-wide significant association for mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures at the sodium channel gene cluster on chromosome 2q24.3 [rs7587026, within an intron of the SCN1A gene, P = 3.36 × 10(-9), odds ratio (A) = 1.42, 95% confidence interval: 1.26-1.59]. In a cohort of 172 individuals with febrile seizures, who did not develop epilepsy during prospective follow-up to age 13 years, and 6456 controls, no association was found for rs7587026 and febrile seizures. These findings suggest SCN1A involvement in a common epilepsy syndrome, give new direction to biological understanding of mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures, and open avenues for investigation of prognostic factors and possible prevention of epilepsy in some children with febrile seizures.

Rare deletions at 16p13.11 predispose to a diverse spectrum of sporadic epilepsy syndromes.

Deletions at 16p13.11 are associated with schizophrenia, mental retardation, and most recently idiopathic generalized epilepsy. To evaluate the role of 16p13.11 deletions, as well as other structural variation, in epilepsy disorders, we used genome-wide screens to identify copy number variation in 3812 patients with a diverse spectrum of epilepsy syndromes and in 1299 neurologically-normal controls. Large deletions (> 100 kb) at 16p13.11 were observed in 23 patients, whereas no control had a deletion greater than 16 kb. Patients, even those with identically sized 16p13.11 deletions, presented with highly variable epilepsy phenotypes. For a subset of patients with a 16p13.11 deletion, we show a consistent reduction of expression for included genes, suggesting that haploinsufficiency might contribute to pathogenicity. We also investigated another possible mechanism of pathogenicity by using hybridization-based capture and next-generation sequencing of the homologous chromosome for ten 16p13.11-deletion patients to look for unmasked recessive mutations. Follow-up genotyping of suggestive polymorphisms failed to identify any convincing recessive-acting mutations in the homologous interval corresponding to the deletion. The observation that two of the 16p13.11 deletions were larger than 2 Mb in size led us to screen for other large deletions. We found 12 additional genomic regions harboring deletions > 2 Mb in epilepsy patients, and none in controls. Additional evaluation is needed to characterize the role of these exceedingly large, non-locus-specific deletions in epilepsy. Collectively, these data implicate 16p13.11 and possibly other large deletions as risk factors for a wide range of epilepsy disorders, and they appear to point toward haploinsufficiency as a contributor to the pathogenicity of deletions.

Dravet syndrome: new potential genetic modifiers, imaging abnormalities, and ictal findings.

PURPOSE: Dravet syndrome is an autosomal dominant epileptic encephalopathy of childhood, which is caused mainly by SCN1A and PCHD19 mutations. Although Dravet syndrome is well recognized, the causes of acute encephalopathy are still elusive, and reported data on ictal electroencephalography (EEG) and structural brain abnormalities are scarce. METHODS: We studied 30 children who fulfilled the clinical criteria for Dravet syndrome. All patients were screened for SCN1A mutations and 25 for POLG mutations with bidirectional sequencing. Clinical data, including etiologic studies done as part of the clinical workup, were collected from hospital charts. Ictal video-EEG recordings and magnetic resonance (MR) images were reanalyzed by the authors. KEY FINDINGS: SCN1A mutations were found in 25 patients (83%). Two SCN1A mutation-negative patients had chromosomal translocations involving chromosomes 9 and X, and one had a mutation in PCDH19. Prolonged seizures were associated with acute encephalopathy in three SCN1A mutation-positive patients. One showed evidence of a significant hypoxic-ischemic event during status epilepticus. The other two demonstrated new persistent neurologic deficits postictally; they both carried heterozygous POLG variants (p.Trp748Ser or p.Gly517Val). Hippocampal sclerosis or loss of gray-white matter definition in the temporal lobe was observed in 7 of 18 patients who had MRI after age 3 years (39%). Motor seizures were recorded on video-EEG for 15 patients, of whom 12 were younger than 6 years at recording; 11 patients (73%) showed posterior onsets. SIGNIFICANCE: Our data imply that a heterozygous X;9 translocation and rare POLG variants may modify the clinical features of Dravet syndrome. The latter may increase susceptibility for acute encephalopathy. Temporal lobe abnormalities are common in patients imaged after 3 years of age. Focal seizures seem to localize predominantly in the posterior regions in young children with Dravet syndrome.

Cognitive impairment in preschool children with epilepsy.

PURPOSE: Studies have shown that underlying pathology and early onset of seizures are both significant factors contributing to cognitive impairment in children with epilepsy. However, there are only few studies focusing on cognitive impairment in preschool children with epilepsy. The purpose of this study was to describe the cognitive performance in a population-based cohort of preschool children with epilepsy. The aims of the study were to determine frequency of cognitive impairment, level of cognitive functions, and epilepsy-related factors correlating with cognitive impairment. METHODS: The study group consisted of a population-based cohort (N = 64) of preschool children (3-6 years 11 months) with active epilepsy. Medical data and results from previous psychological evaluations were reviewed retrospectively from the medical records. A logistic regression model was used for the prediction of cognitive impairment. KEY FINDINGS: Prevalence of epilepsy was 3.2 per 1,000 children. Cognitive function was considered to be within normal or borderline range for 50%, mildly retarded for 22%, and moderately to severely retarded for 28%. Cognitive impairment was related to complicated epilepsy, age at onset of epilepsy, abnormal magnetic resonance imaging (MRI), and additional neurologic problems. Age at the onset of seizures was the only significant predictor of cognitive impairment. SIGNIFICANCE: The results concur with those of earlier studies on cognitive impairment in childhood epilepsy. Age at onset of epilepsy is also an important factor for cognitive impairment on young children with epilepsy. The results suggest that cognitive impairment is evident early in the course of epilepsy.

Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study.

Partial epilepsies have a substantial heritability. However, the actual genetic causes are largely unknown. In contrast to many other common diseases for which genetic association-studies have successfully revealed common variants associated with disease risk, the role of common variation in partial epilepsies has not yet been explored in a well-powered study. We undertook a genome-wide association-study to identify common variants which influence risk for epilepsy shared amongst partial epilepsy syndromes, in 3445 patients and 6935 controls of European ancestry. We did not identify any genome-wide significant association. A few single nucleotide polymorphisms may warrant further investigation. We exclude common genetic variants with effect sizes above a modest 1.3 odds ratio for a single variant as contributors to genetic susceptibility shared across the partial epilepsies. We show that, at best, common genetic variation can only have a modest role in predisposition to the partial epilepsies when considered across syndromes in Europeans. The genetic architecture of the partial epilepsies is likely to be very complex, reflecting genotypic and phenotypic heterogeneity. Larger meta-analyses are required to identify variants of smaller effect sizes (odds ratio<1.3) or syndrome-specific variants. Further, our results suggest research efforts should also be directed towards identifying the multiple rare variants likely to account for at least part of the heritability of the partial epilepsies. Data emerging from genome-wide association-studies will be valuable during the next serious challenge of interpreting all the genetic variation emerging from whole-genome sequencing studies.

Severer phenotype in Unverricht-Lundborg disease (EPM1) patients compound heterozygous for the dodecamer repeat expansion and the c.202C>T mutation in the CSTB gene.

BACKGROUND/AIMS: Unverricht-Lundborg disease (EPM1) is caused by mutations in the cystatin B (CSTB) gene. Most patients are homozygous for the expanded dodecamer repeat mutation alleles, but 9 other EPM1-associated mutations have also been identified. We describe the clinical, cognitive and imaging characteristics of 5 Finnish EPM1 patients who are compound heterozygous for the dodecamer repeat expansion and the c.202C>T mutations. METHODS: Five compound heterozygous patients and 21 patients homozygous for the expansion mutation, participating in an ongoing nationwide clinical and molecular genetics study, were evaluated using the Unified Myoclonus Rating Scale test and comprehensive neuropsychological testing. All patients underwent MR imaging. The MR data were also compared with those of 24 healthy control subjects. RESULTS: Age at onset of symptoms was significantly lower in the compound heterozygotes than in the homozygous EPM1 patients. They also had severer myoclonus and drug-resistant tonic-clonic seizures. Moreover, they had lower cognitive performance. In MRI a voxel-based morphometry analysis of primary and premotor cortex, supplementary motor cortex and thalami revealed gray matter volume loss when compared with the healthy controls, similar to patients homozygous for the expansion mutation. CONCLUSION: Patients compound heterozygous for the dodecamer repeat expansion and the c.202C>T mutations seem to have a severer form of EPM1 than patients homozygous for the expansion mutation. These findings have implications for counseling of EPM1 patients with different genetic defects.

[Seizures in newborn infant]. / Vastasyntyneiden kohtausoireet.

Seizures in newborn infants are common. The may constitute a neurologic emergency or a nonepileptic, harmless symptom. Diagnostics is becoming more specific with current methodologies. Detailed description of seizures and their connection with EEG abnormalities are the diagnostic cornerstones. The treatment has made slow progress, but newer antiepileptic drugs may aid in the treatment of epileptic seizures in newborn infants in the future. For the time being, evidence-based research results for them are lacking, as well as data on long-term effects. Differential diagnosis of seizures has become increasingly important.

[Video-EEG in epilepsy diagnostics--when and why?]. / Video-EEG epilepsian diagnostiikassa--milloin ja miksi?

Video-EEG (V-EEG) refers to the recording of video picture simultaneously with EEG. A major part of epilepsy patients have to be diagnosed without V-EEG. For a patient having recurrent seizures, the aim is to accomplish V-EEG recording during a seizure. Of the indications of V-EEG, the most important one is diagnosis and differential diagnosis of epilepsy. V-EEG is able to differentiate epileptic seizures from cardiogenic seizures, motor disorders or functional seizures, for example. Essential clinical indications include a more exact classification of epilepsies, evaluation of therapeutic response, and localization of the seizure focus prior to epilepsy surgery.

[Update on current care guidelines. The treatment of status epilepticus]. / Pitkittynyt epileptinen kohtaus.

Status epilepticus is a medical emergency. Most epileptic seizures last for 1-4 minutes and seizures lasting over five minutes, should be treated as status epilepticus. EEG is essential for diagnostics and the monitoring of treatment effect. The treatment for status epilepticus, irrespective of aetiology, can be divided into first-aid medications, such as buccal midazolam or rectal diazepam, first-line medications such as intravenous diazepam or lorazepam, and second-line medications such as fosphenytoin and valproate for adults and phenobarbital for children. Third-line treatment is suppressive general anaesthesia, monitored by continuous EEG. Antiepileptic medication of patients with epilepsy should be carefully re-evaluated after episode of status epilepticus.

Atypical Pattern of Frontal EEG Asymmetry for Direct Gaze in Young Children with Autism Spectrum Disorder.

This study examined approach-motivation related brain activity (frontal electroencephalogram [EEG] asymmetry) in response to direct and averted gaze in 3- to 6-year-old typically developing (TD) children, children with autism spectrum disorder (ASD), and those with intellectual disability (ID). We found that, in TD children, direct gaze elicited greater approach-related frontal EEG activity than did downcast gaze. This pattern of activity was in contrast to that observed in children with ASD, who showed greater approach-related activity in response to downcast gaze than to direct gaze. ID children did not differ in their responses to different gaze conditions. These findings indicate that another person's direct gaze does not elicit approach-motivation related brain activity in young children with ASD.

An assessment of the Irish population for large-scale genetic mapping studies involving epilepsy and other complex diseases.

The recent completion of the International HapMap Project has rapidly advanced our understanding of linkage disequilibrium (LD) in the human genome. Today, tagging SNPs (tSNPs) can be quickly and easily selected and consequently HapMap data are regularly applied to both small- and large-scale genetic mapping studies. However, to correctly interpret the application of HapMap-derived tSNPs in a genetic mapping study, an understanding of how well HapMap data represents LD in the study population is critical. The Irish population had not previously been characterised in this way. Here, we do so using a set of 4424 SNPs selected from 279 candidate genes for epilepsy genotyped across 1118 healthy individuals from the Irish, British, Finnish and Australian populations. By considering the Irish population alongside surrounding European populations, our results confirm that the HapMap European-derived population accurately estimates patterning of LD in European descent populations. The Irish population appears notably well matched to the European HapMap population, and is markedly similar to the neighbouring British population. Although we were unable to detect significant substructure within the Irish population (a favourable result for genetic mapping), methods for controlling stratification should always be incorporated. This analysis therefore confirms that the genetic architecture of the Irish population is well suited to the study of complex traits and that tSNPs selected using the HapMap data can be confidently applied to the Irish population.

Visual and Hearing Impairments After Preterm Birth.

OBJECTIVES: Our aim was to determine and compare the incidences of sensory impairments among very preterm (VP) (<32 + 0/7 weeks), moderately preterm (MP) (32 + 0/7-33 + 6/7 weeks), late preterm (LP) (34 + 0/7-36 + 6/7 weeks), and term infants (≥37 weeks) and to establish risk factors of neurosensory disabilities. METHODS: This national register study included all live-born infants in Finland between 1991 and 2008. Infants who died before the age of 1 year, who had any major congenital anomaly, or had missing data were excluded (n = 21 007; 2.0%). A total of 1 018 256 infants were analyzed. Incidences of hearing loss, visual disturbances or blindness, other ophthalmologic disorders, and retinopathy of prematurity were determined for gestational age (GA) groups. Risk factors of hearing loss and visual disturbances or blindness were analyzed. RESULTS: The incidences of sensory impairments decreased with advancing GA at birth (P < .001). The most prominent factors associated with increased risks of hearing loss and visual impairment were intracranial hemorrhage and convulsions. VP (odds ratio [OR] 2.34; 95% confidence interval [CI] 1.75-3.14) and LP (OR 1.26; 95% CI 1.04-1.52) births were associated with an increased risk of hearing loss, and VP (OR 1.94; 95% CI 1.55-2.44), MP (OR 1.42; 95% CI 1.11-1.80), and LP (OR 1.31; 95% CI 1.16-1.49) births predicted an increased risk of visual impairment. CONCLUSIONS: Incidences of sensory impairment decreased with increasing GA at birth. The most prominent risk factors predictive of sensory disabilities were intracranial hemorrhage and convulsions. VP and LP births were associated with an increased risk of hearing loss, and VP, MP, and LP births were associated with an increased risk of visual impairment.

Cystatin B: mutation detection, alternative splicing and expression in progressive myclonus epilepsy of Unverricht-Lundborg type (EPM1) patients.

Progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1) is an autosomal recessive neurodegenerative disorder caused by mutations in the cystatin B gene (CSTB) that encodes an inhibitor of several lysosomal cathepsins. An unstable expansion of a dodecamer repeat in the CSTB promoter accounts for the majority of EPM1 disease alleles worldwide. We here describe a novel PCR protocol for detection of the dodecamer repeat expansion. We describe two novel EPM1-associated mutations, c.149G > A leading to the p.G50E missense change and an intronic 18-bp deletion (c.168+1_18del), which affects splicing of CSTB. The p.G50E mutation that affects the conserved QVVAG amino acid sequence critical for cathepsin binding fails to associate with lysosomes. This further supports the previously implicated physiological importance of the CSTB-lysosome association. Expression of CSTB mRNA and protein was markedly reduced in lymphoblastoid cells of the patients irrespective of the mutation type. Patients homozygous for the dodecamer expansion mutation showed 5-10% expression compared to controls. By combining database searches with RT-PCR we identified several alternatively spliced CSTB isoforms. One of these, CSTB2, was also present in mouse and was analyzed in more detail. In real-time PCR quantification, CSTB2 expression was less than 5% of total CSTB expression in all human adult and fetal tissues analyzed. In patients homozygous for the minisatellite mutation, the level of CSTB2 was reduced similarly to that of CSTB implicating regulation from the same promoter. The physiological significance of CSTB2 remains to be determined.

Multicentre search for genetic susceptibility loci in sporadic epilepsy syndrome and seizure types: a case-control study.

BACKGROUND: The Epilepsy Genetics (EPIGEN) Consortium was established to undertake genetic mapping analyses with augmented statistical power to detect variants that influence the development and treatment of common forms of epilepsy. METHODS: We examined common variations across 279 prime candidate genes in 2717 case and 1118 control samples collected at four independent research centres (in the UK, Ireland, Finland, and Australia). Single nucleotide polymorphism (SNP) and combined set-association analyses were used to examine the contribution of genetic variation in the candidate genes to various forms of epilepsy. FINDINGS: We did not identify clear, indisputable common genetic risk factors that contribute to selected epilepsy subphenotypes across multiple populations. Nor did we identify risk factors for the general all-epilepsy phenotype. However, set-association analysis on the most significant p values, assessed under permutation, suggested the contribution of numerous SNPs to disease predisposition in an apparent population-specific manner. Variations in the genes KCNAB1, GABRR2, KCNMB4, SYN2, and ALDH5A1 were most notable. INTERPRETATION: The underlying genetic component to sporadic epilepsy is clearly complex. Results suggest that many SNPs contribute to disease predisposition in an apparently population-specific manner. However, subtle differences in phenotyping across cohorts, combined with a poor understanding of how the underlying genetic component to epilepsy aligns with current phenotypic classifications, might also account for apparent population-specific genetic risk factors. Variations across five genes warrant further study in independent cohorts to clarify the tentative association.

The incidence and risk factors of epilepsy in children born preterm: A nationwide register study.

OBJECTIVES: The aim was to compare the incidence of epilepsy between very preterm (VP) (<32+0 weeks), moderately preterm (MP) (32+0-33+6 weeks), late preterm (LP) (34+0-36+6 weeks) and term infants (≥37 weeks) and to establish and compare risk factors of epilepsy in these groups. METHODS: The national register study included all live born infants in Finland in 1991-2008. Excluding infants with missing gestational age, a total of 1,033,349 infants were included in the analysis and they were analyzed in four subgroups (VP, MP, LP and term) and three time periods (1991-1995, 1996-2001 and 2002-2008). RESULTS: 5611 (0.54%) children with epilepsy were diagnosed. The incidence of epilepsy was 2.53% in the VP, 1.08% in the MP, 0.75% in the LP and 0.51% in the term group. Intracranial hemorrhage (OR 3.48; 95% CI 2.47-4.89) and convulsions in the neonatal period (OR 13.4; 95% CI 10.2-17.6) were associated with an increased risk of epilepsy. Compared to the term group, preterm birth (VP OR 4.59; 95% CI 3.79-5.57, MP 1.97; 1.48-2.63, LP 1.44; 1.25-1.68) was associated with an increased risk of epilepsy after adjusting for maternal, pregnancy, delivery and sex variables. CONCLUSIONS: The incidence of epilepsy decreased by advancing gestational age at birth and preterm birth predicted an increased risk of epilepsy in childhood. Intracranial hemorrhage and neonatal convulsions were strongly associated with an increased risk of epilepsy.

Atypical physiological orienting to direct gaze in low-functioning children with autism spectrum disorder.

Reduced use of eye contact is a prominent feature in individuals with autism spectrum disorder (ASD). It has been proposed that direct gaze does not capture the attention of individuals with ASD. Experimental evidence is, however, mainly restricted to relatively high-functioning school-aged children or adults with ASD. This study investigated whether 2-5-year-old low-functioning children with severe ASD differ from control children in orienting to gaze stimuli, as measured with the heart rate deceleration response. Responses were measured to computerized presentations of dynamic shifts of gaze direction either toward (direct) or away (averted) from the observing child. The results showed a significant group by gaze direction interaction effect on heart rate responses (permuted P = .004), reflecting a stronger orienting response to direct versus averted gaze in typically developing (N = 17) and developmentally delayed (N = 16) children but not in children with ASD (N = 12). The lack of enhanced orienting response to direct gaze in the ASD group was not caused by a lack of looking at the eye region, as confirmed by eye tracking. The results suggest that direct gaze is not a socially salient, attention-grabbing signal for low-functioning children with ASD. Autism Res 2017, 10: 810-820. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.